LIGAND-INDEPENDENT AND LIGAND-DEPENDENT FUNCTIONS OF THYROID-HORMONE RECEPTOR ISOFORMS DEPEND UPON THEIR DISTINCT AMINO TERMINI

Isoform specificity likely plays a large role in the ability of the th yroid hormone receptor (TR) to specifically regulate gene expression i n both the presence and absence of its cognate ligand, triiodothyronin e. To investigate further the mechanism of isoform specificity of huma n TRs (TR alpha 1 and TR beta 1), we have examined their functional ef fects on positive thyroid hormone response elements (TREs) both in the presence and absence of ligand. TR alpha 1 was greater than 2-fold mo re potent than TR beta 1 on both TREs studied, in terms of both ligand -independent repression and ligand-dependent stimulation. By creating a number of chimeric and mutant receptors, we have established that th e increased functional potency of TR alpha 1 is due to its unique amin o terminus. Deletion or substitution of the TR alpha 1 amino terminus leads to a loss of both its ligand-independent and -dependent function s on positive TREs. Furthermore, the TR alpha 1 amino terminus antagon izes homodimer formation on the positive TREs studied, TR constructs, which contain the TR alpha 1 amino terminus, are unable to form homodi mers and form exclusively heterodimers with RXR alpha on direct repeat and palindromic TREs. Deletion of the amino terminus from either TR i soform leads to preferential homodimer formation, which suggests that the TR amino terminus is important for relative heterodimerization cap ability. From these data, we conclude that TR alpha 1 isoform specific ity on positive TREs resides predominantly in its amino terminus throu gh its ability to favor heterodimerization with the retinoid X recepto r or other nuclear proteins.